Effectiveness of iodoform-based filling materials in root canal treatment of deciduous teeth: a systematic review and meta-analysis

Abstract Introduction The objective was to review the effectiveness of iodoform-based compared to noniodoform-based filling materials in the root canal treatment of deciduous teeth. Methods This systematic review and meta-analysis used randomized clinical trials with six months or more follow-up. The risk of bias of individual studies and the certainty of the evidence were evaluated (Cochrane risk of bias tool and GRADE, respectively). Results The initial search resulted in 5,127 studies after removal of duplicates. After screening by title and abstract, 34 full-text studies were eligible and 21 remained in the qualitative synthesis and 19 in the meta-analysis. Iodoform-based filling materials resulted in fewer clinical failures when compared to noniodoform-based filling materials at the 6 months (OR = 0.43, 95%CI: 0.19–0.97, p = .04) and 9–12 months (OR = 0.46, 95%CI: 0.23–0.93, p = .03), but not at the 18–30 months follow-up (OR = 1.08, 95%CI: 0.58–2.03, p = .81). When considering radiographic failures, there was no statistical difference between iodoform-based and noniodoform-based filling materials at the 6 months (OR = 0.72, 95%CI: 0.39–1.32, p = .29) and 18–30 months follow-ups (OR = 1.06, 95%CI: 0.51–2.21, p = .87), but fewer radiographic failures were detected at the 9–12 months follow-up (OR = 0.49, 95%CI: 0.29–0.80, p = .005). Conclusion Iodoform-based filling materials showed better clinical and radiographic performance when compared to non-iodoform-based filling materials in the short term, and similar performance in the long term. However, most of the studies exhibited unclear or high risk of bias and the overall certainty of the evidence ranged from low to very low. Therefore, new randomized clinical trials must be accomplished to corroborate this conclusion.


Introduction
Endodontic treatment with complete pulp removalpulpectomy-is commonly used in deciduous teeth with irreversible pulpitis or necrotic pulp [1,2]. Usually, after the chemomechanical preparation of the root canals, an absorbable and biocompatible material must be used to favor repair and allow the permanence of the tooth in the mouth till its physiological exfoliation [1]. In an attempt to simplify the steps, Lesion Sterilization and Tissue Repair (LSTR) therapy has been investigated for the treatment of primary tooth canals. This technique implies nonmechanical preparation of the root canals and placement of a paste made of a mixture of antibiotics at the entrance of the root canals [3].
The complex morphology of root canal systems in primary teeth can hamper mechanical instrumentation, irrigation and/or disinfection [4]. For this reason, the use of substances with antimicrobial properties is generally used to increase the chances of a successful endodontic treatment [1]. Even in LSTR therapy, the use of a mixture of antibiotics is considered sufficient to respond to the periapical lesions [3].
Previous systematic reviews have focused on different filling materials for deciduous teeth after endodontic treatment [4][5][6][7], on the chemomechanical technique or LSTR therapy [3]. However, there is no review investigating possible advantages of iodoform addition to filling materials, independent of the endodontic technique used. The objective this study was to review the effectiveness of iodoform-based compared to non-iodoform-based filling materials in the root canal treatment of deciduous teeth.

Protocol and registration
The study protocol was registered in the PROSPERO database (CRD42019123937), and the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement were followed [41]. The study was accomplished from December 2018 to June 2019 and updated in March 2021.
Information sources and search strategy P (Population) ¼ children with deciduous teeth that received root canal treatment; I (Intervention) ¼ root canal treatment using iodoform-based filling materials; C (Comparison) ¼ root canal treatment using noniodoform-based filling materials; O (Outcomes) ¼ clinical and/or radiographic success/failure; S (Type of studies) ¼ randomized clinical trials.
The search used the following electronic data bases: MEDLINE via PubMeb, Scopus, Web of Science, Latin American and Caribbean Literature on Health Sciences (LILACS), Biblioteca Brasileira em Odontologia (BBO) (Brazilian Dentistry Library) and Cochrane Library.
The search strategy (Supplement 1) was based on controlled vocabulary (MeSH terms) of the PubMed database along with free keywords retrieved from titles and abstracts. MeSH terms and free keywords were initially combined in each item using the Boolean operator 'OR'. The Population and Intervention were combined to build the search strategy by the Boolean operator 'AND'. The search strategy developed for PubMed was adapted to other electronic databases. We also hand-searched the reference lists of all primary studies for additional relevant publications.
The grey literature was searched using the databases System for Information on Grey Literature in Europe (SIGLE) and Scholar Google. Dissertations and theses were searched using the ProQuest Dissertations and Theses Full-Text databases and the Peri odicos Capes Thesis database.

Eligibility criteria
Randomized Clinical Trials (RCT) were included. The studies excluded comprised noncontrolled clinical studies, editorial letters, literature reviews, in vitro or animal studies, observational studies, case reports and case series. Studies written in Chinese and Japanese were also excluded. No restrictions on publication dates were applied.

Study selection and data collection process
The retrieved studies were imported into a reference management software (EndNote X9 -Clarivate Analytics, Philadelphia, USA). After removal of duplicates, studies were excluded after title and abstract reading according to the exclusion criteria previously described. This process was performed independently by two reviewers (M.F.S.J. and A.C.R.C.); in case of disagreement, a third reviewer was consulted (L.M.W.).
The studies were selected by title and abstracts accordingly to the described eligibility criteria. Fulltext studies were obtained when there was insufficient information in the title and abstract to make a clear decision.
Eligible studies received an identification that combined the first author's name and the year of publication. The data from the studies were extracted to customized extraction forms that comprised the study design, participants, interventions and outcomes. Studies reporting different follow-ups of the same research were only considered once to prevent data overlapping. This process was performed independently by two reviewers (M.F.S.J. and A.C.R.C.); in case of disagreement, a third reviewer was consulted (L.M.W.).

Risk of bias in individual studies
The evaluation of the risk of bias of the selected studies was carried out by two independent reviewers (M.F.S.J. and A.C.R.C.), using the Cochrane Collaboration tool to evaluate the risk of bias in RCT [42]. The evaluation criteria comprised five items: (1) sequence generation, (2) allocation concealment, (3) blinding of result evaluators, (4) incomplete result data, and (5) selective result reports. In case of discrepancies between the evaluators, a third reviewer was consulted (L.M.W.).
The risk of bias was rated following the recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. Each criterion was graded as having 'low', 'unclear' or 'high' risk of bias, accordingly to the information retrieved in the text regarding potential bias.
The study was judged as 'high' risk if at least one key domain was not achieved adequately. At the study level, a study was judged as having a 'low' risk of bias if all domains were considered at 'low' risk. If the information could not be retrieved or was incomplete on one of these domains, without presenting a 'high' risk of bias in any domain, the study was considered as having an 'unclear' risk of bias.

Meta-analysis
The outcomes assessed were clinical or radiographic failure (yes or no) for the different follow-ups (6, 9-12 and 18-30 months) and techniques for tooth preparation (chemomechanical and LSTR). The results were summarized using the random-effects model to estimate the Odds Ratio (OR) using a 95% confidence interval (95%CI). The heterogeneity was assessed using the Cochran Q test and the I 2 statistics. All analyses were performed using the software Revman 5 (Review Manager ver. 5, The Cochrane Collaboration, Copenhagen, Denmark). The certainty of the evidence was assessed using the  Grading  of  Recommendations Assessment, Development and Evaluation (GRADE) [43]. This stage was accomplished to determine the overall certainty of the evidence for each meta-analysis. The evidence can be graded in 4 levels (very low, low, moderate, high). When a meta-analysis is graded as 'high quality', it means that the authors are very confident that the true effect lies close to the estimate of the effect.

Selection of studies
The initial search in the databases resulted in 6,049 registers (Supplement 1). The removal of duplicates resulted in 5,127 registers. After the selection based on title, the number of registers was reduced to 96. A total of 62 registers was excluded after the abstract reading, resulting in 34 full text for the eligibility assessment. Thirteen registers were excluded due to: (1) nonrandomized clinical trial [22] (2) absence of a group using iodoform-based filling material [44,45], (3) all groups used iodoform-based filling materials [34,[46][47][48][49], (4) original dissertation of an included study [50], (5) publication of preliminary results of an included study [51,52], and (6) text in Chinese [53,54] (Supplement 2).
The number of follow-up sessions included a minimum of two [9,10,15,28,29] and a maximum of seven [14] clinical and/or radiographic appointments. The interval of between follow-ups sessions varied greatly from 15 days [37] to 30 months [16].

Assessment of the certainty of the evidence
The certainty of the evidence was assessed according to the evaluated outcomes: clinical and radiographic failure in the different follow-up periods (6, 9-12 and 18-30 months) and for the techniques for tooth preparation (chemomechanical and/or LSTR).
For the outcome 'clinical failure', the certainty of the evidence was graded as 'very low' for all followup periods, with the exception of the total (chemicalmechanical technique and LSTR) and LSTR subgroup analysis at the 6 and 9-12 months, which was rated 'low' ( Table 2(A-C)).
For the outcome 'radiographic failure', the certainty of the evidence was graded as 'very low' for all follow-up periods, with the exception of the LSTR subgroup at 9-12 months, which was rated 'low' ( Table 2(A-C)).

Discussion
This systematic review and meta-analysis compared iodoform-based and noniodoform-based filling materials for root canal treatment of deciduous teeth. Iodoform-based filling materials showed fewer clinical failures when compared to noniodoform-based materials after 6 and 9-12 months, and similar performance after 18-30 months. There were fewer radiographic failures of iodoform-based filling materials at the 9-12 months follow-up, but similar performance of the two groups of materials at the 6 and the 18-30 months follow-ups.
The similarity between the filling materials with and without iodoform at the 6 months radiographic evaluation may derive from the insufficient time to detect significant changes in bone neo-formation and lesion healing, particularly when the evaluation criteria were based on visual examination of the radiographs. More sensitive methods, like radiographic subtraction is known to better detect subtle changes in radiopacity that supersede human eye examination capacity [55]. Although they exhibit low heterogeneity, the loss of patients during follow-up was not explained by the authors, resulting in incomplete data outcome and this probably have influence in the results.
All systematic reviews published so far were inconclusive in identifying the best choice of filling material for primary tooth pulpectomy [4][5][6][7]. This systematic review was the first to detect significant differences between different filling materials. This result may indicate a positive effect on the clinical and radiographic outcomes of filling materials containing iodoform, an effect which can be explained by the high antimicrobial property of iodoform [8,10,34]. In general, the odds ratio for the treatment effect was obtained from an adequate sample size and a good number of studies were included. Even so, the  Most of the included studies were judged to be at "unclear risk of bias". b The optimal size effect was not achieved.
c There was heterogeneity that could not be explained.
d The optimal information sample was not met and the confidence interval crosses the threshold.
e All the included studies were judged to be at "unclear risk of bias".
f The included studies were at high and unclear risk of bias.
g There is inconsistency in the direction of the effect.
certainty of the evidence was classified as 'low' or 'very low' for the evaluated outcomes. This limits our confidence, that is, the true effect may be substantially different from the estimate of the effect. The ideal scenario for analyzing the effect of iodoform-based filling material would be a study comparing the same filling material with and without iodoform.
Most studies used commercially available iodoform-based filling materials, such as Vitapex [14][15][16][17][27][28][29], Metapex [9,10,19,20], Endoflas [11,12,18,19,35], RC Fill [16], Zical [21], Maisto paste [13] or Maisto-Capurro paste [30]. Although many professionals choose premixed pastes due to ease of use, the professional must be aware of the material's composition and follow manufacturer recommendations for a greater success rate. Only two studies [37,38] used an unmarketed, iodoform-based filling material in the form of a modified Guedes-Pinto paste. In this situation, the proportions of the components must be respected during handling to obtain the maximum benefit and the lowest risk of adverse effects. The resorption ability is an advantageous property of iodoform [8,10,34]. However, when iodoform-based filling materials are not used correctly, they have the disadvantage of compromising aesthetics through a brown-yellowish pigmentation of the dental crown [34]. To reduce pigmentation, during the performance of the clinical procedure, the operator must be careful cleaning of the pulp chamber after root canal obturation and before restoration.
The application of different eligibility criteria and different clinical protocols during endodontic treatment among the studies may have introduced some degree of variability and have influenced the rates of radiographic and clinical failures. Potentially influencing factors include: selection of the patient and tooth and the operator's ability and preferred technique (manual, motorized files or LSTR). Also, the instrument size and the taper influence the flow of the root canal filling material and the removal of infectious radicular dentin [56]. Incomplete information about such bias factors as observed in the included studies make comparison between studies difficult. To facilitate the comparison between the techniques, subgroup analysis considering the different root canal techniques (chemomechanical root canal preparation and LSTR therapy) was performed.
The LSTR involves the use of a triple antibiotic mixture, i.e. a paste based on ciprofloxacin, metronidazole and minocycline (3Mix-MP) [3,[28][29][30]36,37], aiming to disinfect the root canal system without any mechanical preparation. The performance of iodoform-based filling materials was similar in the chemomechanical technique and the LSTR therapy at the 6 and the 9-12 months clinical evaluations, and in the radiographic analysis at 6 months. The iodoformbased filling material was superior only in the radiographic comparison at the 9-12 months of follow-up. Another systematic review has previously demonstrated that the two treatments showed comparable outcomes, regardless of the follow-up period (6, 12 or 18 months) and type of evaluation (clinical or radiographical) with certainty of evidence ranging from very low to moderate [3].
It must be pointed out that the absence of difference in our metanalysis may be due to the limited number of studies and a small sample size that probably failed to identify differences between groups; also the certainty of evidence was graded as low and very low. Even so, it is worth noting that a simplified technique such LSTR can benefit professionals, as it will reduce clinical time and facilitate the treatment of non-collaborative children [3]. For this reason, future studies with the use of LSTR are encouraged and should compare not only the techniques used, but include test groups with and without iodoform even with the chemomechanical technique.
As recommended in systematic reviews about filling materials in deciduous teeth [3][4][5][6][7], there has been an increase in the number of randomized clinical trials in the last few years [9,11,12,17,20,21,27,29,30,[35][36][37][38]. But it is relevant to point out that the quality of the trials was not improved sufficiently to strengthen the scientific evidence. This highlights the importance of best design and methodological accuracy of the primary studies, particularly regarding the randomization process and blinding of evaluators. Thus, further studies are still needed to increase the certainty of the evidence.

Conclusion
Iodoform-based filling materials showed better clinical and radiographic performance when compared to noniodoform-based filling materials in the short term and similar performance in the long term. However, most of the studies showed unclear or high risk of bias and the overall certainty of the evidence ranged from low to very low. Therefore, new randomized clinical trials must be accomplished to corroborate this conclusion.